Mycophenolate mofetil inhibits differentiation, maturation and allostimulatory function of human monocyte-derived dendritic cells

Abstract

SUMMARYWe have studied the effect of mycophenolate mofetil (MMF), a new drug used in prevention of transplant rejection, on differentiation, maturation and allostimulatory activity of human monocyte-derived dendritic cells (MDDC). MDDC were generated in vitro with granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-4 in the presence or absence of MMF. MMF reduced the number of immature MDDC in culture, dose-dependently, by inducing apoptosis and inhibited their stimulatory activity on allogeneic lymphocytes. These changes correlated with down-regulation of costimulatory and adhesion molecules such as CD40, CD54, CD80 and CD86. No differences were observed in mannose receptor (MR)-mediated endocytosis, measured by the uptake of fluorescein isothiocyanate (FITC)-dextran. MDDC differentiated in the presence of MMF showed significantly reduced maturation upon stimulation with lipopolysaccharide, as judged by lower expresson of CD83 and co-stimulatory molecules, lower production of tumour necrosis factor (TNF)-a , IL-10, IL-12 and IL-18 as well as lower stimulation of alloreactive T cells including naive CD4 + CD45RA + T cells. In contrast, MDDC matured in the presence of MMF showed a more marked decrease in the FITC-dextran uptake than mature MDDC cultivated without MMF and the phenomenon correlated with downregulation of the MR expression. These results suggest that MMF impairs differentiation, maturation and function of human MDDC in vitro , which is an additional mechanism of its immunosuppressive effect.

Modulation of Dendritic Cells for Tolerance Induction*

“…Mehling et al [25] reported that MMF directly affects DC maturation and impairs their capacity to induce a cell-mediated immune response in vivo. The findings of this study indicate a novel role of the enzyme IMPD in DC activation, which was recently confirmed by another group [26]. As regards the calcineurin inhibitors CsA and FK 506, Lee et al [27] suggested that CsA interfered with DC maturation via NF-κB inhibition, while other studies have failed to demonstrate significant effects of CsA on the maturation of monocyte-derived DC [19] or on epidermal Langerhans cell function [28].…”

Mycophenolic acid in Rheumatology: mechanisms of action and severe adverse events

“…Similarly to what previously observed in murine models of delayed contact hypersensitivity (26), also in human monocyte-derived DCs, MPA (10 µM) reduces the surface expression of costimulation and interaction molecules (CD40, CD54, CD86, CD80, CD83) and cytokine production (TNFα, IL-12, IL-18) (27). Moreover, TNFα-stimulated DCs incubated with MPA (100 µM) do not acquire maturation morphologic features and continue to express immature cell receptors, like CXCR1 (28).…”

Impact of Mycophenolic Acid on the Functionality of Human Polymorphonuclear Neutrophils and Dendritic Cells during Interaction with Aspergillus fumigatus

“…Killing assays with A. fumigatus germlings (ATCC 9197) (8 ϫ 10 4 ; multiplicity of infection [MOI] ϭ 1) were performed as described previously (12). MPA (10 M; Novartis, Germany) was administered for 3 h at 37°C.…”